We propose to conduct a genetic-epidemiologic study of familial colorectal cancer. Probands with colorectal cancer will be ascertained from population-based cancer registries in Imperial, Orange, and San Diego counties in Southern California. Based on family history information available in the registry, we will identify and recruit approximately 130 families that report a history of at least three cases of colorectal cancer in two generations. More detailed pedigree information will be obtained via a telephone interview. From these families, we will identify 80 multiple-case families that are judged to be potentially the most informative for linkage analyses, based on a simulated lod score criterion (using SIMLINK). Each member of these linkage-informative families will be asked to provide one sample of blood for DNA analyses and to complete questionnaires on risk factors for colorectal cancer. Efforts will be made to verify all reported cancers and all causes of death. For cases with colorectal cancer or any other cancer, we will obtain pathology reports and tumor blocks. Our objectives are to 1) identify the familial colon cancer (FCC) gene on chromosome 2; 2) study the effects of other putative risk factors for colon cancer, including diet, physical activity, nonsteroidal anti-inflammatory drugs, and hormones; 3) study gene- environment interactions, with a focus on factors that affect the expression or penetrance of the FCC gene; and 4) define sources of heterogeneity (i.e., what variables discriminate between families that do or do not involve the FCC gene). The primary analytical technique is linkage analysis that incorporates information on environmental covariates. In linked families, informative recombinants for fine mapping of the FCC locus will be identified. In unlinked families we will look for alternative pathways. This proposed study is Project 1. Project 2 focuses on gene-environment interactions in colorectal polyps. Project 3 focuses on the molecular genetics of colorectal polyps and cancer. The molecular work for this study will be conducted as a part of Project 3.